Nature Neuroscience: Dissociable Control of Motivation and Reinforcement by Distinct Ventral Striatal Dopamine Receptors

Dopamine transmission is essential for reward processes including motivation and reinforcement. Motivation is the internal process activating and directing behavior, and reinforcement increases the likelihood of a behavior through stimulus–response and action–outcome associations. The nucleus accumbens medial shell within the striatum serves as a key hub for reward-related behaviors, receiving dopaminergic inputs from the ventral tegmental area. Motivation and reinforcement are coordinated to maximize reward outcomes and are implicated in psychiatric disorders such as substance use and mood disorders. However, important questions remain concerning how motivation and reinforcement are regulated at the molecular level—including the question of what dopamine receptors in the nucleus accumbens medial shell are responsible for regulating these reward-related behaviors. 

To answer these vital questions, investigators including Juan Enriquez-Traba, PhD (National Institute of Mental Health), Hugo Tejada, PhD (National Institute of Mental Health), and Zachary Freyberg, MD, PhD (Associate Professor of Psychiatry and Cell Biology), investigated how dopamine release within the striatum translates into cellular changes through its actions on specific dopamine receptors to drive distinct aspects of reward function. Using genetics, anatomical tracing, slice electrophysiology, and circuit-level manipulations of dopamine receptor function, the scientists examined the receptor signaling of a previously understudied dopamine receptor, the D3 receptor, in the nucleus accumbens medial shell in mice exposed to a rewarding stimulus. 

In a paper published in Nature Neuroscience, the investigators identified distinct roles for nucleus accumbens medial shell D3 receptors and D1 receptors in regulating different features of D1- medium spiny neuron physiology underlying complementary aspects of reward-related behaviors. Activation of D3 receptors, but not D1 receptors, inhibits GABAergic transmission within local microcircuits to promote effort-based motivation to engage in a rewarding stimulus. 

“These studies have disentangled the respective contributions of two key striatal dopamine receptors, D1 and D3 receptors, to different aspects of reward. The aim is to ultimately apply this knowledge to better understand and treat addiction,” said Dr. Freyberg, co-corresponding author the paper.

Dissociable control of motivation and reinforcement by distinct ventral striatal dopamine receptors
Enriquez-Traba J, Arenivar M, Yarur-Castillo HE, Noh C, Flores RJ, Weil T, Roy S, Usdin TB, LaGamma CT, Wang H, Tsai VS, Kerspern D, Moritz AE, Sibley DR, Lutas A, Moratalla R, Freyberg Z, Tejada HA.
Nature Neuroscience 28, 105–121 (2025). https://doi.org/10.1038/s41593-024-01819-9